Posted on Authorea 12 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160253804.44054844/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. rhpdcHospital Orthopedic 23 22 21 20 19 18 Angeles 17 Los at California 16 15 Angeles Los at 14 California of University 13 12 School Medical 11 10 9 8 7 6 Permanente 5 4 3 2 1 aataShirVergano Schrier Samantha Henderson Kl¨ocknerChiara Ahmed Syed Hueffmeier Ulrike spectrum molecular and phenotypic the expanding EIF3F Moran Nelson Ward Isum Faivre io Hospital Dijon GAD U1231 medicine INSERM of school university, Medicine Emory of School University Kaiser Emory Group, Medical Permanente California Southern Baystate Genetics, – of School Department Medical Massachusetts of University Friedrich-Alexander-Universit¨at Erlangen-N¨urnberg Erlangen-Nuremberg University Friedrich-Alexander Erlangen-Nuernberg Friedrich-Alexander-Universitaet lnclGntc,Hsefl hlrnsHsia tNULnoe Y Langone, NYU Langone, NYU at Hospital Children’s Hassenfeld Genetics, Clinical Fakultat Medizinische Freiburg Erlangen-Nurnberg Genetics Friedrich-Alexander-Universitat Human for Center SYNLAB Queensland Angeles of Los University Angeles, Los University at Center Leipzig California Medical of Leipzig University of Medicine, University of of School University Geffen Medicine, David of School Geffen David Medicine, Laboratory and Pathology Medicine Laboratory and Angeles Pathology Los Medicine, California of of School University Geffen David Pediatrics, of Department Genetics, of Division Johnson Wood Health Robert Sanford Rutgers Pediatrics, of Department Genetics, Medical of Division TRANSLAD Comt´e, FHU Bourgogne-Franche Universit´e de 9 23 16 rdrcTa a Them Mau Tran Frederic , onPappas John , CAClfri etrfrRr Disease Rare for Center California UCLA , rltdnuoeeomna iodr eietn and delineating disorder: neurodevelopmental -related 26 12 ioh Palculict Timothy , 5 aiaDutra-Clarke Marina , rsy Rawson Kristyn , 18 1 ui MacGaughran Julie , onlaKraus Cornelia , 24 nikRothschild Annick , 27 rc Wahl Erica , 5 26 ienBarr Eileen , ueiMullegama Sureni , 10 2 13 hitn Botti Christina , iimReuter Miriam , uinMartinez-Agosto Julian , 20 28 ure Kohlhase Juergen , Andr´e Reis , 25 6 1 ogLi Hong , ai ule Sacoto Guillen Maria , 17 1 11 26 tffnUebe Steffen , i Zacher Pia , ua Brooks Susan , od Elloumi Houda , 7 29 neln bruel ange-line , n hitaeZweier Christiane and , 21 aa Schuhmann Sarah , 14 aeLee Hane , 18 aiAo Jamra Abou Rami , 3 ayAieAbbott Mary-Alice , 26 11 Lindsay , aty Burns Kaitlyn , 26 8 d Reich Adi , Laurence , 15 Stanley , 30 22 Ellen , 26 , 12 19 , 4 , , Posted on Authorea 12 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160253804.44054844/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. eae hntpcsetu nti ru n eciea diinl ofrurpre disease-causing unreported far so homozygosity additional, with an individuals describe unreported and group previously confirm we this 21 Thus, in of variant. c.694T spectrum variant group phenotypic the a for related assembled heterozygosity we compound study, or a current suggesting the 2018), al., ho- In et and heterozygous (Martin cells both Furthermore, iPSC in 2018). mechanism. rates al., pro- et translation cell (Martin reduced Cate, variants rates in mozygous & proliferation involved reduced Kranzusch, c.694T mRNAs and the (Lee, levels for of protein apoptosis homozygous group be and to 2007). specific differentiation gene-edited Imataka, three (iPSC), highly control, & Yokoyama, in cycle a Sonenberg, loss cell Masutani, to hearing 2015; including binds sensorineural growth, which or and eIF3 problems liferation factor behavioral initiation and 2018). same al., six, translation the et in carried (Martin families occurred respectively seven epilepsy individuals, from individuals, individuals all affected nine in All 67). 2018). of al., recessive analysis homozygous burden et autosomal recessive (Martin disorder, exome-wide diagnosis developmental large molecular a intellectual by identified #618295: were Variants (OMIM (NDD) disorder opmental the in variants Bi-allelic Introduction tone. EIF3F or- study delay, Our speech correlation. Keywords milestones, genotype-phenotype motor some to suggesting regard of head, in and spectrum spectrum molecular body the and of phenotypic growth of individual the heterozygous postnatal end expands severe and compound pre- the the and in neither at problems Symptoms were although variant ganic observed, distinctive. and truncating were obviously features additional symptoms stature. were dysmorphic an gastrointestinal short appearance Minor with and general lip/palate, nor loss, cleft spectrum. facial develop- hearing phenotypic pain, individuals’ the tone, speech to the of muscular delayed sensitivity part altered reduced including are problems, microcephaly, delays symptoms behavioral that ophthalmological developmental had suggests individuals had study affected individuals this the affected Moreover, of All half spec- About variant. molecular ment. founder and a phenotypic was the p.(Phe232Val) c.694T expand for and disability, (1/21) delineate intellectual To variable heterozygous by characterized hearing-loss. disorder, of sensorineural neurodevelopmental trum and a problems with individuals behavioral nine epilepsy, in causative in as variant reported missense homozygous identical An Abstract 2020 12, October 30 29 28 27 26 25 24 nttt fHmnGntc,FidihAeadrUiest Erlangen-Nuremberg Friedrich-Alexander-University Genetics, Human of Institute Erlangen Hospital Genetics University of Division Daughters Pediatrics, King’s UBMD The of Hospital Children’s GeneDx center Medicine medical of Sheba School University York New EIF3F ee erdvlpetldsre,sotsaue efes eairldffiute,atrdmuscular altered difficulties, behavioral deafness, stature, short disorder, neurodevelopmental gene, EIF3F rltdnuoeeomna iodr eeaie 1aetdidvdas ooyos(02)o compound or (20/21) homozygous individuals, affected 21 examined we disorder, neurodevelopmental -related isnevratc.694T variant missense EIF3F EIF3F > /p(h22a)in p.(Phe232Val) G/ eehv eetybe ulse stecuefrasnrmcneurodevel- syndromic a for cause the as published been recently have gene dfiinya eaieypeaetcuefratsmlrcsieNDD. autosomal-recessive for cause prevalent relatively a as -deficiency EIF3F EIF3F > dnie hog ag-cl eoewd eunigapoc,was approach, sequencing genome-wide large-scale a through identified , /p(h22a) eievral nelculdsblt (ID) disability intellectual variable Beside p.(Phe232Val). G/ EIF3F EIF3F rltdsnrmcnuoeeomna disorder. neurodevelopmental syndromic -related > > altp nlssi 2fmle ugse htc.694T that suggested families 12 in analyses Haplotype . 2 /p(h22a) efrhrdlnaethe delineate further We p.(Phe232Val). G/ /p(h22a)vrat eosrtdlwrEIF3F lower demonstrated variant, p.(Phe232Val) G/ noe nesnilsbnto h ags eukaryotic largest the of subunit essential an encodes nvitro In tde fidcdpuioetse cells stem pluripotent induced of studies > ,0 aiiswt oprevious no with families 4,500 loss-of-function EIF3F > G/ - Posted on Authorea 12 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160253804.44054844/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. h eaeidvda ffml 2hdtomlclrdanss nadto otehomozygous the to addition In diagnoses. molecular two (length had protein P2 truncated a had a family she or of variant, structure. decay individual altered mRNA with female in 8) The either of was subsequently 6 and and exon 2020), frameshift 20%, al., et by a missense (Karczewski reduced in (gnomAD) inherited Database result Aggregation maternally to Genome the predicted the in for absent families. heterozygous was 16 variant of compound latter one (parents was in variant reported (P3) the c.694T was of individual consanguinity variant Parental carriers affected testing). heterozygous for additional were available parents not An were tested (P16) All 16 1). pedigree (Figure of families 16 from c.694T variant individuals missense homozygous same the identified We identified haplotypes members, the family of core one other to Results deduced in be genotypes could available data. rs12420464) to (rs79714374, P17 WES due P4 of 1,818 in individual P17 in SNPs affected respectively. P10, two the of of rs12421289, in ones individuals rs12420464 and the and single and rs12420464 rs79714374 in by of inferred and tagged P10 be be of a could mother could had in genotypes rs12278319 rs56392532) of their and was homozygous Genotypes WES, (rs79714374 SNP the 1,818 SNPs seven with in tagged of disequilibrium individuals redundantly set Some affected The (11/12). other of parents 3.5-53.4%. coverage in their between available, haplotypes frequencies be if the with to and assess identified haplotypes were different to of rs56392532) six used block rs12420464, for and as LD rs4758267, SNPs 2001) 2005) the Donnelly, Daly, rs7941782, tagging Within & & rs12278319, Smith, 2009). Maller, (Stephens, rs12421289, al., Fry, vs.2.1.1 (rs79714374, et (Barrett, PHASE (Huffmeier Haploview using previously basis in the individual described of (LD)” covering an definition disequilibrium at P14) the linkage haplotypes of using determined of individual blocks spine affected haplotype “solid one defined We and model (hg19)). P13 (chr11:7,614,107-8,413,933 of regions 1. parents Table flanking and or Supportive individual in project, (MAF presented affected SNPs research frequent as samples, a 136 members, within of family or genotypes core test used in We clinical testing a co-segregation as for age performed sequencing older sequencing, Sanger genome for by whole al. or et (WES) Kromeyer-Hauschild sequencing by reported studies and EIF3F “https://www.pedz.de/” (2006) data-source al. used. available et were characteristics Voigt publicly (2001) clinical by the groups detailed data age, collect birth corresponding to on the based used was to team circumference) clinical bi-allelic head patient’s with individuals the affected by of out legal filled to the questionnaire or A according Parents conducted 2018). were al., Investigations et Methods enrollment. (Martin before principles. of consent Helsinki authors and of informed 2015), Declaration corresponding Hamosh, written the & gave Valle, as Schiettecatte, guardians (Sobreira, such GeneMatcher collaborations, through gathered internal was group study The institutions. contributing individuals the Affected of boards Friedrich-Alexander-Universit ethics the local of committee by ethical and the by approved was study The considerations ethical and policies Editorial Methods ainswr dnie ysqecn fats/itleta iaiiygn aes hl exome whole panels, gene disability intellectual autism/ of sequencing by identified were variants < 0 naetdidvdaso 2 3 6 1,P2 1 Tbe2,btdet eyhg linkage high very to due but 2), (Table P17 P12, P10, P6, P3, P2, of individuals affected in 10x > /p(h22a)adaptral neie ain .6dp .Gn8Aase1) The p.(Gln288AlafsTer14). c.861dup/ variant inherited paternally a and p.(Phe232Val) G/ enovo de rmsitvratin variant frameshift EIF3F ains onraiebd esrmns(egt egtand weight (height, measurements body normalize To variants. > MECP2 % eeae rmitra E aa(,1 independent (1,818 data WES internal from generated 5%) 3 mlctdi etsnrm OI #312750). (OMIM syndrome Rett in implicated , > /p(h22a)in p.(Phe232Val) G/ EIF3F v fsvncmo SNPs common seven of five , EIF3F EIF3F tErlangen-N ¨ at (NM isnevariant missense EIF3F 074 n21 in 003754) urnberg, ¨ n its and EIF3F Posted on Authorea 12 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160253804.44054844/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. eepnlfrsotsaueadtsigfrRse-ivrsnrm OI 106) h niiulcom- individual a The including #180860). thrive (OMIM to syndrome failure Russel-Silver or for stature testing and short were stature for short features diagnostics gestalt. for Dysmorphic targeted facial panel received individ- individuals. gene recognizable initially affected four a all had abundant in considered in individuals by noted not even Two was were embedded fairly crease and were (= fissures palmar non-specific encased palpebral single and or Also, unilateral subtle antev- and/ generally A 1). The and Table short tip 2). 2, ears, nasal each. (Figure (Figure pointed rotated nails individual uals a toe posteriorly single nose, and observed narrow a finger variant also or skin) in minor We and/ observed a tubular were nares. defect. a (considered erted heart included 2C) lip findings congenital (Figure of dysmorphic a fistula prevalent groove and More nasal problems a and gastrointestinal a of lip had and (P5) Cleft individual 2C,D) combination heterozygous problems. Figure or compound feeding lip, (P3) neonatal Fallot cleft and of of disease, diarrhea tetralogy reflux and gastro-esophageal (P15), constipation included palate which alternating the problems swallow, Notably, microcephalic. gastrointestinal to and 40%) had measurement. age difficulties (24%) (4/10; last for individuals the microcephaly short the birth. examination of both and and at Five was last birth length 32%), P3 the between body of (6/19; normal consistent at individual examination had remained heterozygous stature examination), physical Sup- 60%) compound last short last 1, (6/10; the with (Table the at normocephaly examination individuals and at or physical birth seven common at last the and was length the of hypotonia Microcephaly body at of four truncal individuals data Interestingly, of available affected (with combination of 1). 40% a noted, Table in tone, was portive observed muscular atrophy was muscle altered stature proband, with Short one individuals In ten diagnosed. was sensitivity. developed the extremities pain third of hypertonic an reduced the two and have psychosis, while in to 21 and abilities, while noted (P11.1), meningioma speech were years of meningioma. their 2.5 individuals combination a Two of a lost on had age these operated P14 was an of (P16) at attention. Two individual more individuals additional demanded 21 (P14). and of Epilepsy adulthood swings three in mood problems. in and sleeping observed (P4.1) was had (38%), years abilities (24%) hyper-/myopia cognitive individuals five included of 21 (3/20). in Regression of and individuals findings Five of (8/21) nonspecific 15% ophthalmological revealed (38%). individuals in different imaging individuals diagnosed affected Notably, Brain was affected of (5%). examined was (10/21). 38% coloboma 13 hypertonia and individuals of to or (5%) affected up nystagmus problems, hypo- of (14%), (12/21; in social Muscular strabismus probands 48% observed disorder, the in pica. were compulsory of diagnosed or obsessive findings half and aggressivity as than common such More deficit, problems also attention (12/21). hyperactivity, behavioral individuals have autism, affected to anxiety, of observed 57% remaining were in the 57%) reported in was language individual, usable loss but heterozygous Hearing simplified, compound and the words including few examination between heterozy- last widely individuals. varied compound the abilities with at speech individual speech while developed single not The in- had 1). ascertained (5/21) Table ( of Supportive 33% sitting months, 18 gous milestones, unassisted motor ([?] in walking Considering delays independent delays. exhibited developmental (4/12) had dividuals of age individuals age average 12.1 an affected The had was (P14). All individuals examination case four another physical years; in last 8.5 suspected the of asphyxia median of perinatal oligohydramnios time and although uneventful, (P9), the largely syndrome) pregnancy at were Rett 1. one deliveries with Table and in individual Supportive pregnancies the noted of excluding in was history when details Overall, total presented males. (14 females but 7 15 and 1), were (Table individuals aspects reported the clinical Among of summary the in individual this in symptoms As EIF3F ains(3 i o akidpnetya h g f5yas u rwe.2%o individuals of 24% crawled. but years, 5 of age the at independently walk not did (P3) variants EIF3F rltdNDcnieal vra ihtoei etsnrm,w i o include not did we syndrome, Rett in those with overlap considerably NDD -related > 4 8years. 18 ± > . er ma / tnaddvain,wt a with deviation), standard +/- (mean years 9.6 0mnh)ad7%o niiul 1/0 in (14/20) individuals of 70% and months) 10 Posted on Authorea 12 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160253804.44054844/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. pk oeta e od,wieaqatro ffce niiul a osec eeomn.Haigloss Hearing development. varied speech individuals ID no of of had majority individuals degree the affected the phenotype: of Similarly, the quarter to a age. delay while speech words, normal walking significant few learned a of than individuals at finding more most the spoke milestones while adds independently, motor study walk achieved This to individuals widely. developmental learn some Motor not and did degree. variable patient late, alleles of one delay developmental both variable: global on was had delay individuals variants affected truncating all com- study, that this are ex- In who speculate life. is individuals with might affected compatible v2.1.1 one further be gnomAD variants, of not in truncating and might variants for individuals truncating c.694T heterozygous in two with for alleles pound individuals homozygous truncating of of individuals lack Regarding being number in of overall function (probability the low EIF3F causing tremely note, residual threshold Of possibly harmful in a certain p.(Phe232Val). variants and heterozygous a compound correlation reach variants with might phenotype individual missense the they c.694T rare in as of phenotype Other severe harmful, case in less effects. remains as or comparable it irrelevant NDD have rate, functionally might translational variants reduced be and missense might rate other proliferation whether decreased stability, speculative in amount/ variant protein missense reduced identical in variant the missense Haplotype region. the only of localized Iraqi. nascence As more the and a while French, haplotype, Jewish, to founder including determined Ashkenazi a origins be on Russian, Asian event cannot West mutational Ukranian, single European/ a Bulgarian, of support German, spectrum analyses wide Scottish, a Irish, of p.Phe508del individuals English, affected e.g. Partic- in diseases: identified in was backgrounds. genetic variants other regional truncating certain and population-specific in ethnical and observed heterogeneous, been with in have variant cohort variants a pathogenic et Therefore, in common (Anazi causative. particularly ularly reported are For in variants NDDs, been variant truncating have in NDDs. predominantly missense families diseases, finding recessive of frequent those handful autosomal rather In a identical, other or 2017). an most al., few Non-Finnish et only for in Reuter NDDs, than especially 2017; recessive gnomAD, al., higher autosomal in other is carriers the individuals, heterozygous of many c.694T Jewish of variant frequency Askenazi shared The and the 2018). European to al., et due the (Martin NDD, that viduals with finding variant. individuals the founder of add a cohorts study indicating five this haplotype, to its in single contrast a with performed EIF3F in on analyses variant, line once haplotype this In arose The for probably homozygous variants. 2020). most frequent be al., variant more to et six reported (Karczewski was the (0.12%) gnomAD of in individuals individual European no non-Finnish pathogenicity, and (0.21%) Jewish 7 the c.694T variant of missense role gous relevant a confirms This study Our analyses. haplotype 2). performed (Table variant we Discussion founder recurrently, a or suggesting pedigrees, once tested arose all etiology. variant one different the and missense of that epilepsy, the of revealed with and whether have unrelated to test likely reported To are was symptoms father overlapping Those One migraines. overlapped asymptomatic. mother mainly X-syndrome) Fragile were carriers syndrome, 2018). Heterozygous al., (Angelman et individuals (Martin affected previously in reported performed those was that testing for heterozygous pound th a rvosyrpre ob n ffwgnssgicnl nihdfrb-lei eoye nlarge in genotypes bi-allelic for enriched significantly genes few of one be to reported previously was otcommon most CFTR EIF3F ncsi boi nErpas ouainseicvrat in variants population-specific Europeans, in fibrosis cystic in EIF3F EIF3F ain a na dnia altp mnml78k)i 3aetdidvdasof individuals affected 13 in kb) 7.8 (minimal haplotype identical an on was variant > /p(h22a)(atne l,21) ncnrs,tefidn fterather the of finding the contrast, In 2018). al., et (Martin p.(Phe232Val) G/ > isnevrati nmD(.7)wt ihs rqece nAshkenazi in frequencies highest with (0.07%) gnomAD in variant missense /p(h22a)i l u n ffce niiul hsvratrepresents variant This individual. affected one but all in p.(Phe232Val) G/ ainspeetdwt nrueiegot eadto.Ms te genetic other Most retardation. growth intrauterine with presented variants loss-of-function EIF3F EIF3F nsnrmcND eosre h aeptoei homozy- pathogenic same the observed We NDD. syndromic in GJB2 noeat=09,osre vrepce ains=0.07). = variants expected over observed 0.97, = intolerant EIF3F a enfntoal hrceie n hw oresult to shown and characterized functionally been has ndans.I hssuy the study, this In deafness. in 5 nams l ffce niiul sa uncommon an is individuals affected all almost in > /p(h22a)i l ffce indi- affected all in p.(Phe232Val) G/ EIF3F HFE ugsssm genotype- some suggests EIF3F nhemochromatosis, in isnevariant missense > G/ Posted on Authorea 12 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160253804.44054844/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. od ga lom n d ec r mlye fGnD,Ic l te uhr elr ohv no have to declare authors other All Inc. Statement Availability GeneDX, Data of employees Mullegama, are V. Sureni Reich interest. Advancing Palculict, of Adi Blake Timothy conflict and for Henderson, Elloumi B. Center Lindsay Zghal Sacoto, Houda Guillen National J. Maria NIH authors The the number by grant Diseases. Interest (CTSI) Rare of supported for Institute Conflict Center Science was California Translational previous UCLA 9 and the the and Clinical of family UL1TR001881 author UCLA data (NCATS) for corresponding study. the Science the common sequencing enabled Translational as our study to Martin genome the collaborators C. in referring Whole Hilary for participation thank (GeneDx) whose also Torti families We Erin and and study, analyses. individuals the affected and all collection to grateful are We feet. and hands nose, short ears, Acknowledgements symptoms, the ophthalmological of loss, anomalies hearing minor tone, and muscular speech stature, delayed altered delay, developmental difficulties, reported global features. behavioral include previously as recurrent development, features frequent, the ears Characteristic NDD. more rotated confirms autosomal-recessive as of posteriorly study 2018), cause nails al., nares), toe this et anteverted and summary, (Martin finger tip, In nails encased nasal appear- toe or pointed facial dysplastic and/ distinctive nose, previously and short obvious been fingers (tubular as not an tapered well findings had recognize indicated two nasal not had latter observed did the study we we those, previous study, Of the previous fistula. While the nasal ance. with and agreement defect heart In palate, described. and height. lip indicated the than cleft of data tract, centiles part longitudinal nal the be while might along cohort, that course this features constant Rare within more degree was a variable Microcephaly had of group. growth and study head this stature that in short observed symptoms commonly than cause. those was frequent independent whether the adulthood, another less an until to and have In occurring as size might also conclusions cohort stature, or allow Short meningioma. The spectrum not in with disease meningioma. did the of individuals encephalopathy individual of of diagnosis individuals an part majority the disorder: three are the in to syndromic of led the psychosis ages this also of and young frequency to relatively two deficiency seizure However, related increased B12 of necessarily an three vitamin prognosis. individual, not in with for observed are relevant individual was that be years) an diagnoses might ˜30 which to additional (2.5 individuals had ages affected various 20 at the reveal neurodegeneration the or not of regression did muscular component Developmental essential imaging atrophy/ an muscular brain represent in study, sequencing) of indicative exome work-up. previous diagnostically finding or diagnostic de- considered the the (genome previously not approaches with did this sequencing therefore concordance as genome-wide were with In and 2018), association findings an al., individual. specific supports et another study (Martin in common this symptom hypoplasia are in rare they sensitivity however as pain deficiency, findings, scribed, reduced ophthalmologic EIF3F of to study’s observation related this The be to necessarily regard reduced population. not In and general might mice the myopia) 2019). wild-type in (hyper-/ al., muscular to these compared et are study of atrophy (Docquier murine study muscle some activation a amplified this pathway eIF3f of in MTOR support murine Results observed the and of phenotype depletion symptoms problems. human partial sleeping unreported the cause: with and far concordance findings reported so some ophthalmologic initially indicate frequent, than might hypertonia, Other frequent or less and/ was 2018). hypotonia epilepsy al., whereas findings, et common (Martin were difficulties behavioral and EIF3F eae D nld ucinlpolm ftegastrointesti- the of problems functional include NDD related 6 EIF3F isnevrata eaieyfrequent relatively a as variant missense loss-of-function EIF3F eae D.Thus, NDD. related steunderlying the as Posted on Authorea 12 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160253804.44054844/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. e niaenme fidvdaswt vial nomto nti etr n ecnae.Det an to Due paranthe- in percentage). (number and feature feature this specified on the information of with available diagnosis families with confounding individuals individuals/ additional of of number number indicate the ses bi-allelic indicates with row individuals Each of features Clinical 1: (2006). Table M. T. K. Schneider, & Tables C., Renken, N., doi:10.1055/s-2006-924458 . Rochow, 956-970. Deutschland. K., , Bundesrepublik Hartmann, reconstruc- der D., haplotype Neugeborenenkollektivs des for Olbertz, . Analyse method C., statistical Fusch, new M., A Voigt, Apr). . (2001, data. P. 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A., depletion Haploview: Alkuraya, Raibon, eIF3f L., (2005). Pavlin, . J. A., M. Docquier, Daly, . & J., . Maller, maps. A., B., haplotype Fry, Alhashem, C., S., J. Alsahli, Barrett, T., disability. intellectual Y. of Asi, heterogeneity doi:10.1007/s00439-017-1843-2 V., genetic the Salpietro, Expanding article. S., this (2017). of Maddirevula, material S., supplementary the Anazi, in available are study this of References findings the supports that data The iifrais 21 Bioinformatics, netDrao,129 Dermatol, Invest J MOJ 26 J, EMBO mJHmGnt 68, Genet, Hum J Am 597 Physiol, J cec,362 Science, 2,263-265. (2), MECP2 aue 522 Nature, 1) 3338.doi:10.1038/sj.emboj.7601765 3373-3383. (14), 61) 1116.doi:10.1126/science.aar6731 1161-1164. (6419), 1) 1733.doi:10.1113/JP277841 3107-3131. (12), rltddsre naetdidvda fP n h issue the and P2 of individual affected in disorder -related u ua,36 Mutat, Hum 2,3538 doi:10.1038/jid.2008.233 355-358. (2), 978-989. 75) 1-1.doi:10.1038/nature14267 111-114. (7554), 7 oascrf idrelud,149 Kinderheilkunde, Monatsschrift EIF3F 1) 2-3.doi:10.1002/humu.22844 928-930. (10), AAPyhar,74 Psychiatry, JAMA euthleudFaehikne 66 Frauenheilkunde, und Geburtshilfe variants. u ee,136 Genet, Hum 1-2,1419-1429. (11-12), 3,293-299. (3), 8,807-818. (8), aue 581 Nature, Posted on Authorea 12 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160253804.44054844/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. atonetnlsmtm 2;2% n.a. 86%) (7; 6 n.a. 24%) (21; 5 ears rotated posteriorly nose 33%) of (9; findings features 3 facial fine Dysmorphisms 43%) symptoms (7; Gastrointestinal 3 form) minor (incl. palate lip/ 33%) cleft (9; Malformations later 6 stature short (%) 15%) later (20; microcephaly 24%) 3 birth (21; at 5 stature short birth at microcephaly measurements Body psychosis 57%) (21; 12 meningioma encephalopathy issues neurological Other confirmed 38%) - (13; Epilepsy 5 of problems no. Sleeping (total 57%) findings (21; study nonspecific 12 48%) Current imaging (21; Brain 10 coloboma nystagmus strabismus hyper-/myopia findings Ophthalmological (44%) hypertonia 4 hypo-/ (56%) Muscular 5 loss Hearing problems Behavioral 0%) (7; 0 Feature regression speech no delay (32%) speech 7 delay (68%) developmental 15 global Development asphyxia perinatal delivery premature pregnancy eventful delivery pregnancy/ (median) years examination in last at age Average 6%) (17; male 1 female Gender symptoms neurological with Parents - variants) (bi-allelic sibling(s) Affected - history Family consanguinity Parental p.(Phe232Val) c.694T for homozygous Feature no.: No./ applicable; not further n.a. no including; but incl.: categories, four individuals; first affected the indiv.: for only aff. number. individual this Abbreviations: considered aspects. we phenotypes, overlapping of EIF3F > G/ 2;1% 9 11%) (9; 1 (20; 7 25%) (20; 35%) 5 11%) (19; 2 10%) (20; 2 (19; 40%) 6 (20; 20%) 8 (15; 32%) 3 40%) n.a. (10; 4 5%) (21; 1 10%) (21; 2 5%) (21; 1 (21; 5%) 1 (21; 14%) 1 (21; 5%) 3 38%) (21; 8 indiv.) of percent aff. data; with indiv. 14%) (21; 5 3 100%) 24%) (21; (21; 21 100%) (21; 21 suspected) 5%; (19; 1 10%) 2 (20; oligo-hydramnios) 5%; (21; 100%) 1 (9; 9 12.1 6%; migraines) (34; or parents epilepsy 2 24%) (17; 4 94%) (17; 16 indiv.) of percent aff. data; with of indiv. no. (total study Current ± . 85 16.3 (8.5) 9.6 8 n.a. (4; 1 13%) (8; 1 25%) n.a. 0%) (1; 0 11%) (9; 1 et 2018) (Martin al., indiv.) percent aff. data; of with indiv. of no. (total study Published n.a. n.a. n.a. 100%) (9, 9 0%) (9; 0 0%) (9; 0 prenatal scan) abnormal 11%; (9; 1 7%; (14; ID) parent mild 1 22%) (9; 2 et 2018) (Martin al., indiv.) percent aff. data; of with indiv. of no. (total study Published ± 34(13.0) 13.4 Posted on Authorea 12 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160253804.44054844/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 1 CCCG / [C]CACCGC / CCACCGC / [C]CACCGC / CCACCGC / CCACCGC P12 / CCACCGC P11 / [c]CACC[g]C P10 / [C]CACCGC P9 / [C]CACCGC P7 / CCACCGC P6 P4 P3 P2 P1 control 1,818 in Pedigree haplotypes from respectively. P4 applicable. in rs12421289, not [brackets] = and in n.a rs12420464 lowercase pedigree, in by = ones tagged P the be and Abbreviation: could members WES. family P17 core genotypes P12, their other disequilibrium, P10, in linkage P6, high very P3, in to P2, Genotypes due but a of rs79714374 coverage, of had low individuals Genotypes a variant, in Germany. had missense from [brackets] WES rs7941782, in the control rs56392532 house-internal rs12278319, harboring and independent, rs12421289, C-C-A-C-C-G-C 1,818 in rs79714374, Haplotype 3.5% of used: frequency rs56392532. were and SNPs rs12420464 intragenic rs4758267, seven analyses, haplotype For at Haplotypes 2: Table of no. (total study Current feet flat fingers/ toes slender or feet hands/ short clinodactyly) (shortness, 5 or abnormality and/ toes fingers of nails encased or set deep Dysmorphisms Feature Feature { te brackets other th ne/toe finger/ EIF3F ffce niiul...mte (frequency mother . . . individual affected . . . [C]CACCGC CCACCGC [C]CACCGC CCACCGC CCACCGC CCACCGC [c]CACC[g]C [C]CGACGC [C]CACCGC CCACCGC . . in. haplotypes of Combination } ol eifre nsnl niiul fP0 1 u oaalbegenotypes available to due P17 P10, of individuals single in inferred be could n1 pedigrees. 13 in 2;3% 2;1% (20; 15%) 5 (20; 15%) 3 (20; 25%) 3 30%) (20; 6 indiv.) of percent aff. data; with indiv. indiv.) of percent aff. data; with of indiv. no. (total study Current § 9 f2 of TCT (0.047) TTGCTTT / CCACCGC (0.534) CCACTGC / CCACCGC (n.a.) [C]C[x]CTG[C] [C]C (0.534) CCACTGC / CCACCGC (0.124) CTGCTGT / CCACCGC (0.095) [C]CGCCGC / [C]CACCGC (0.095) [c]CGCC[c]C / [c]CACC[g]C (0.534) [C]CACTG[C] / [C]CACCG[C] (0.534) [C]CACTGC / [C]CACCGC (0.534) CCACTGC / CCACCGC . . in. haplotypes of Combination nd { A } haplotype) C[]/ CCG[C] n.a. et 2018) (Martin al., indiv.) percent aff. data; of with indiv. of no. (total study Published et 2018) (Martin al., indiv.) percent aff. data; of with indiv. of no. (total study Published f2 of (frequency father . . . CCCG (0.534) [C]CACTGC / [C]CACCGC (0.534) CCACT[G]C / CCACC[G]C (0.534) [C]CACTG[C] / [C]CACCG[C] (0.095) CCGCCGC / CCACCGC (0.035) CCACCGC / CCACCGC (0.158) [C]CGACG[C] / [C]CACCG[C] (0.534) [c]CACT[g]C / [c]CACC[g]C (0.534) [C]CACTG[C] [C]CGACG[C] (0.158) [C]CGACGC / [C]CACCGC (0.124) CTGCTGT / CCACCGC . . in. haplotypes of Combination nd haplotype) § / Posted on Authorea 12 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160253804.44054844/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ersn 3a y - 5a y3,J 1 t2 m n ,MP3a y2.Sm affected Some 2m. 3y at information P13 clinical M detailed with L, 1 and Table by 8m, Supporting embedded 2y information: nails at Supporting (= P12 nails nails. encased K toe have short J, files individuals and Additional 3m, most nails feet; finger bi-allelic 4y the and carrying at have of hands Note individuals P5 predominantly individuals of skin), affected affected E-I backs view. (D). All puffy 5y, four lateral correction have at of at 8m. after individuals and 6y age P3 feet (C), at for represent and surgery P15 prominent D before Hands M rather P5 L, is in 3: and which lip Figure 2m left tip 3y at nasal groove at pointed and P13 a fistula J,K nasal fissures, 8m, palpebral 2y bi-allelic even at carrying fairly individuals P12 affected I six H, of respectively, profiles facial lateral variants. and Frontal 2: Figure pedigree. P: delay; developmental pedigree. of P: carriers individual. with heterozygous families as 17 identified of Pedigrees 1: / Figure CCACCGC legends Figure / CCACCGC § P17 P14 P13 Pedigree .6dp .Gn8Aase1)i nteudrie altp nP feunyo .5 ncontrols). in 0.158 of (frequency P3 in haplotype underlined the on is p.(Gln288AlafsTer14) c.861dup/ , ersn 3a y 5a madDEP t4 m , hwP t1yada 17y, at and 13y at P9 show F,G 3m, 4y at P5 D,E and 4m at P5 C 5y, at P3 represent A,B + niiulwt nadditional, an with individual : { { CCACCGC CCACCGC . . in. haplotypes of Combination C C } } CACC CACC EIF3F { { G G } } C / C EIF3F ains 3i h aiywt h opudheterozygous compound the with family the is P3 variants. 10 rltdNDD. -related oWSN WES No (0.124) CTGCT[G]T / CCACC[G]C WES No (0.095) CCGCCGC / CCACCGC . . in. haplotypes of Combination env MECP2 novo de l aet,btteoe fP6were P16 of ones the but parents, All ain.Abeitos DD: Abbreviations: variant. EIF3F CCG (0.534) CCACTGC / CCACCGC (0.534) CCACTGC / CCACCGC . . in. haplotypes of Combination variants. EIF3F A- Posted on Authorea 12 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160253804.44054844/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 11